US4131678A - Urapidil/furosemide compounds, compositions and use - Google Patents

Urapidil/furosemide compounds, compositions and use Download PDF

Info

Publication number
US4131678A
US4131678A US05/767,214 US76721477A US4131678A US 4131678 A US4131678 A US 4131678A US 76721477 A US76721477 A US 76721477A US 4131678 A US4131678 A US 4131678A
Authority
US
United States
Prior art keywords
urapidil
furosemide
component
combination
combination according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US05/767,214
Inventor
Hermann Amschler
Kurt Klemm
Gerhard Ludwig
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Takeda GmbH
Original Assignee
Byk Gulden Lomberg Chemische Fabrik GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Byk Gulden Lomberg Chemische Fabrik GmbH filed Critical Byk Gulden Lomberg Chemische Fabrik GmbH
Application granted granted Critical
Publication of US4131678A publication Critical patent/US4131678A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical

Definitions

  • USP 3,957,786 (corresponding to German Specification 1,942,405) concerns piperazinylalkylaminouracils (and their salts with inorganic or organic acids) which exhibit hypotensive activity superior to that of previously-known antihypertensive agents.
  • exploratory clinical testing established that the title compound of Example 4, 1,3-dimethyl-4-( ⁇ -[4-(o-methoxyphenyl)piperazinyl( 1)]-propylamino)uracil (urapidil), is particularly well suited for treating hypertension.
  • urapidil therapy achieved blood-pressure normalization in only about half of the patients with essential and secondary hypertension (of different degrees of gravity) to whom it was administered.
  • the compatibility of this hypotensive agent failed to fulfil all expectations.
  • a product yielding a higher rate of blood-pressure normalization is required for wide therapeutic application.
  • the maximum hypotensive activity of urapidil is increased and the side effects and toxicity of urapidil are reduced in addition to increasing the incidence of blood-pressure normalization of mammals afflicted with hypertension and to whom urapidil is administered.
  • the combined product constitutes a hypotensive agent which is effective and compatible for wide therapeutic application.
  • the combination of furosemide with urapidil is optionally a chemical combination (e.g. in the form of an acid-addition salt) and/or a physical combination (in the form of an admixture or two distinct and separate components). If the urapidil is in the form of a physical combination with furosemide, it is optionally in the form of a pharmacologically-acceptable acid-addition salt with an appropriate (organic or inorganic) acid.
  • Such acids are well known and are exemplified in the noted patent (cf. column 8, first complete paragraph), the entire disclosure of which is incorporated herein by reference.
  • a preferred example is the hydrochloride.
  • the furosemide is in the form of a physical combination with urapidil, it is optionally in the form of a compatible and physiologically-acceptable salt (such as an alkali-metal, e.g. sodium or potassium, or ammonium salt) with a suitable base.
  • a compatible and physiologically-acceptable salt such as an alkali-metal, e.g. sodium or potassium, or ammonium salt
  • such combination is useful as a hypotensive agent. It is preferably administered orally in virtually any of the dosage forms suitable for such mode of administration.
  • the combination is readily formulated into medicaments as the "active ingredient" thereof. When medicament compositions are so formulated, they contain an effective concentration of the noted combination for the route of administration for which the provided dosage form is designed.
  • the "active ingredient" upon which the subject invention is based is a chemical and/or physical combination of urapidil with furosemide.
  • the chemical combination is the 1:1 acid-addition salt combining one mole of urapidil with one mole of furosemide.
  • urapidil/furosemide acid-addition salt it is optionally physically combined with additional urapidil(or a pharmacologically-acceptable acid-addition salt thereof) and/or furosemide(or a physiologically-acceptable salt thereof).
  • Physical combinations include all admixtures as well as forms in which the essential components are separate and distinct.
  • An example of the latter is a dosage form in which one component is in a substrate and the other is in a coating on the substrate.
  • This type of dosage form is known and is prepared from the subject components in essentially the same manner as from other active ingredients.
  • Preferred combinations are those which contain the respective components of the active ingredient in a molar ratio of urapidil:furosemide in the range of from 5:1 to 1:5. Of these combinations, those having a ratio of such components in the range of from 3:1 to 1:3 are of particular interest, and those in which the ratio is 1:1 are outstandingly important.
  • the invention also relates to a method for treating hypertension in mammals, particularly in humans, which comprises administering a therapeutically-effective amount of the active ingredient according to the invention or of a medicament containing the active ingredient to a living organism, e.g. a male or female patient, afflicted with high blood pressure.
  • Such medicament is optionally in any standard dosage form suitable for a recognized mode of administration. It is preferably administered orally or parenterally injected, e.g., subcutaneously, intramuscularly or intravenously.
  • Pharmaceutical preparations based on the active ingredient are advantageously in unit dosage form adapted for the desired mode of administration.
  • a unit dose is, e.g. a tablet, a capsule or a measured volume amount of a powder, a granulate or a solution.
  • Unit dose in the sense of the present invention, is a physically-specified unit which contains an individual amount of active ingredient (combination of urapidil with furosemide) in admixture with a pharmaceutical diluent therefor or together with a pharmaceutical excipient.
  • the amount of active ingredient is selected so that one or more units are usually enough for an individual therapeutic administration.
  • the unit dose is optionally subdivisible, e.g. in the case of tablets provided with grooves, when only a fraction, such as a half or a quarter, of the subdivisible unit is needed for a single therapeutic administration.
  • compositions according to the invention contain, when they are present in unit dosage form, a total of from 5 to 150, advantageously from about 25 to 100 and, in particular, from about 40 to 70 , milligrams (mg) of active ingredient.
  • Therapeutic administration of such pharmaceutical preparations is effected 1 or several, e.g. three, times daily, e.g. after each meal and/or in the evening. Administration may, however, particularly in the case of application as a maintenance dose, be effected only on every second day.
  • the actual dose administered is governed by the frequency of administration, by the duration of treatment, by the nature and gravity of the illness and by the weight, age and state of health of the subject.
  • the daily (oral) dose for mammals e.g. humans, lies between about 0.1 and 1.0 mg of active ingredient per kilogram (kg) of body weight.
  • the pharmaceutical preparations generally comprise active ingredient according to the invention and non-toxic, pharmaceutially-acceptable medicament excipient (used as additive in solid, semi-solid or liquid form or as surrounding agent, for example in the form of a capsule, a tablet coating, a bag or other container for the therapeutically-active constituent).
  • An excipient optionally serves, e.g., as intermediary for the uptake of the medicament by the body, as formulation auxiliary, as sweetener, as flavoring, as coloring matter or as preservative.
  • Oral dosage forms include tablets, dragees, hard and soft capsules (e.g. of gelatin), dispersible powders, granulates, aqueous and oily suspensions, emulsions, solutions and syrups.
  • Tablets contain inert diluents, e.g. calcium carbonate, calcium phosphate, sodium phosphate or lactose; granulating or distributing agent, e.g. maize starch or alginate; binder, e.g. starch, gelatin or acacia gum; and/or lubricant, e.g. aluminum or magnesium stearate, talc or silicone oil. They are optionally additionally provided with a coating which, e.g., is of such a nature that it causes delayed dissolving and resorption of the medicament in the gastro-intestinal tract and thus, e.g., better compatibility or an extended duration of action.
  • inert diluents e.g. calcium carbonate, calcium phosphate, sodium phosphate or lactose
  • granulating or distributing agent e.g. maize starch or alginate
  • binder e.g. starch, gelatin or acacia gum
  • Gelatin capsules contain, e.g., the active ingredient in admixture with a solid diluent, e.g. calcium carbonate or kaolin, or an oily diluent, e.g. olive oil, arachis oil or paraffin oil.
  • a solid diluent e.g. calcium carbonate or kaolin
  • an oily diluent e.g. olive oil, arachis oil or paraffin oil.
  • Illustrative suspending agents are, e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia gum; dispersing and wetting agents include, e.g., polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylenesorbitol mono-oleate, polyoxyethylenesorbitan mono-oleate and lecithin; preservatives comprise, e.g., methyl or propyl hydroxybenzoates; sucrose, lactose, dextrose and invert sugar syrup are typical of flavoring and sweetener.
  • Oily suspensions contain, e.g., arachis oil, olive oil, sesame oil, coconut oil or paraffin oil and thickener, such as beeswax, hard paraffin or cetyl alcohol, in addition to sweetener, flavoring and antioxidant.
  • arachis oil olive oil, sesame oil, coconut oil or paraffin oil
  • thickener such as beeswax, hard paraffin or cetyl alcohol
  • Powders and granulates which are dispersible in water optionally contain the active ingredient in admixture with dispersing, wetting and suspending agents, e.g. those previously mentioned, as well as with sweetener, flavoring and coloring matter.
  • Emulsions contain, e.g., olive oil, arachis oil or paraffin oil besides emulsifier, such as acacia gum, gum tragacanth, phosphatide, sorbitan mono-oleate, polyoxyethylenesorbitan mono-oleate, and sweetener and flavoring.
  • emulsifier such as acacia gum, gum tragacanth, phosphatide, sorbitan mono-oleate, polyoxyethylenesorbitan mono-oleate, and sweetener and flavoring.
  • the different dosage forms are prepared according to well-established procedures by substituting the instant active ingredient in the desired amount for that in corresponding medicament compositions based on other active ingredients having similar or different pharmacological activity.
  • the medicaments are administered as sterile solutions, e.g., isotonic salt solutions comprising dispersing and/or wetting agents and/or pharmacologically compatible diluting agents, as for example kollidon. They are optionally bottled in the form of continuous intravenous drip bottles for continuous intravenous administration.
  • the active ingredient and medicament containing same are very well suited for therapeutic application. Exploratory tests on male and female patients with hypertension (varying in origin and differing in degree of gravity) resulted in normalizing blood pressure in the majority of hypertensive persons to which the active ingredient was administered. Further, superiority (compared to urapidil) of medicament according to the invention was observed with regard to increased activity maximum, reduced side effects, e.g. urine excretion and electrolyte excretion, and reduced toxicity. The active ingredient and medicament according to the invention therefore represent a substantial advance in the treatment of hypertension.
  • the preparation of the active ingredient is effected according to processes which are known per se to one skilled in the art.
  • the 1:1 furosemide salt of urapidil is obtained by direct reaction of equimolar amounts of furosemide and urapidil dissolved in suitable solvents.
  • suitable solvents include aliphatic alcohols, such as methanol, ethanol and ethyl cellosolve; chlorinated hydrocarbons, such as methylene chloride and chloroform; aliphatic carboxylic acid amides or nitriles, such as dimethyl formamide, dimethyl acetamide and acetonitrile; aliphatic ketones, such as acetone and methyl ethyl ketone; or mixtures thereof.
  • the 1:1 urapidil/furosemide is, however, also obtained by resalting, e.g. by reaction of an appropriate urapidil salt, such as a hydrohalide, preferably the hydrochloride, with a suitable salt of furosemide, such as an alkali-metal salt, preferably the sodium salt, or the ammonium salt.
  • an appropriate urapidil salt such as a hydrohalide, preferably the hydrochloride
  • a suitable salt of furosemide such as an alkali-metal salt, preferably the sodium salt, or the ammonium salt.
  • the starting materials, dissolved in suitable solvents are added to one another. Sufficient differences in solubility between the strating product and end product are essential, and the inorganic salt formed as a by-product, e.g. sodium chloride, should be readily separable.
  • Suitable solvents for the resalting are, for example, water, lower aliphatic alcohols (such as methanol and ethanol), aliphatic ketones (such as acetone and methyl ethyl ketone), carboxylic acide amides or nitriles (such as dimethylformamide, dimethylacetamide and acetonitrile) or mixtures thereof with water.
  • lower aliphatic alcohols such as methanol and ethanol
  • aliphatic ketones such as acetone and methyl ethyl ketone
  • carboxylic acide amides or nitriles such as dimethylformamide, dimethylacetamide and acetonitrile
  • the invention relates to combinations (physical and/or chemical) of urapidil and furosemide, to medicaments (including pharmacologically-acceptable hypotensive compositions) containing such combinations and useful for reducing the blood pressure of mammals afflicted with hypertension and to a method of treating hypertension in mammals, particularly humans, by administering to a living afflicted organism, such as a male or female patient, a therapeutically-effective amount of such a combination or of a medicament containing same.
  • the amount of active ingredient administered and, therefore, to be metabolized, i.e. the active ingredient loading of the patient, is greatly reduced.
  • the medicament according to the invention therefore represents a substantial advance in the treatment of hypertension.
  • the compounds or mixtures are administered daily, by means of oesophageal sound, in the stated doses on the stated number of consecutive days, to, in each case, eight rats (OKAMOTO strain) with genetically caused hypertension.
  • the measurement of the blood pressure was effected, in each case, 2, 6 and 24 hours after administration of the substance.
  • the measurement of the systolic blood pressure was effected with the aid of an inflatable cuff place around the tail root, on which cuff there are arranged distally annularly 3 piezoelectric crystals (at a distance of 120° ) for registering the pulse waves.
  • the determination of the blood pressure was effected by inflation of the cuff and graphic recording of the pulse amplitude.
  • the animals were kept in, and the experiments were carried out in, an ambience of 26° C and an atmospheric humidity of 60%. To accustom them to the measuring process, the animals were habituated to the measuring process 2 - 3 times daily for three days.
  • the rats were put into tunnel-shaped wire cage; one narrow side of the cages is slidable, the other has an opening for the taking through of the tail.
  • the body of the animals is protected from direct irradiation by plastic disks which are arranged about 10 cm above the cages.
  • the salt according to the invention has an excellent antihypertensive action with a dose at which the component urapidil, exhibits only a slight effect and the component, furosemide, exhibits no effect.
  • the salt exhibits, according to Table 1, a synergistic, i.e. a superadditive, action compared to that of the individual constituents.
  • the combinations have the advantage that they -- because of their reduced doses of urapidil -- do not show the side effects of urapidil, e.g. sedation, but do exert a pronounced antihypertensive action.
  • the compounds and mixtures were suspended by ultrasonic methods in 1% strength solution of Tylose. Of the suspensions, in each case 40 ml/kg were administered to, in each case, 5 female albino mice (NMRI).

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Furan Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

A combination of urapidil and furosemide, e.g., in the form of an acid-addition salt, in the form of a physical admixture or in the form of two distinct components collectively constitutes an effective active ingredient in the treatment of hypertension. The combination is advantageously incorporated in a standard dosage form and administered by various routes to mammals afflicted with high blood pressure. By combining furosemide with urapidil on one of the noted forms, the maximum hypotensive activity of urapidil is increased, while the side effects and toxicity of urapidil are reduced.

Description

BACKGROUND
USP 3,957,786 (corresponding to German Specification 1,942,405) concerns piperazinylalkylaminouracils (and their salts with inorganic or organic acids) which exhibit hypotensive activity superior to that of previously-known antihypertensive agents. Of the compounds actually named therein, exploratory clinical testing established that the title compound of Example 4, 1,3-dimethyl-4-(γ-[4-(o-methoxyphenyl)piperazinyl( 1)]-propylamino)uracil (urapidil), is particularly well suited for treating hypertension. However, further testing revealed that urapidil therapy achieved blood-pressure normalization in only about half of the patients with essential and secondary hypertension (of different degrees of gravity) to whom it was administered. At the same time, the compatibility of this hypotensive agent failed to fulfil all expectations. A product yielding a higher rate of blood-pressure normalization is required for wide therapeutic application.
SUMMARY OF THE INVENTION
By combining furosemide with urapidil, the maximum hypotensive activity of urapidil is increased and the side effects and toxicity of urapidil are reduced in addition to increasing the incidence of blood-pressure normalization of mammals afflicted with hypertension and to whom urapidil is administered. The combined product constitutes a hypotensive agent which is effective and compatible for wide therapeutic application.
The combination of furosemide with urapidil is optionally a chemical combination (e.g. in the form of an acid-addition salt) and/or a physical combination (in the form of an admixture or two distinct and separate components). If the urapidil is in the form of a physical combination with furosemide, it is optionally in the form of a pharmacologically-acceptable acid-addition salt with an appropriate (organic or inorganic) acid. Such acids are well known and are exemplified in the noted patent (cf. column 8, first complete paragraph), the entire disclosure of which is incorporated herein by reference. A preferred example is the hydrochloride.
If the furosemide is in the form of a physical combination with urapidil, it is optionally in the form of a compatible and physiologically-acceptable salt (such as an alkali-metal, e.g. sodium or potassium, or ammonium salt) with a suitable base. Irrespective of the precise form of urapidil and/or furosemide in the combination of the two, the relevant equivalent amounts of the respective components of the combination is controlling over the enhancement of the hypotensive effect of urapidil imparted to it by the furosemide combined therewith.
Whatever the form of the combination of furosemide with urapidil, such combination is useful as a hypotensive agent. It is preferably administered orally in virtually any of the dosage forms suitable for such mode of administration. The combination is readily formulated into medicaments as the "active ingredient" thereof. When medicament compositions are so formulated, they contain an effective concentration of the noted combination for the route of administration for which the provided dosage form is designed.
DETAILS
The "active ingredient" upon which the subject invention is based is a chemical and/or physical combination of urapidil with furosemide. The chemical combination is the 1:1 acid-addition salt combining one mole of urapidil with one mole of furosemide.
Even when the urapidil/furosemide acid-addition salt is employed, it is optionally physically combined with additional urapidil(or a pharmacologically-acceptable acid-addition salt thereof) and/or furosemide(or a physiologically-acceptable salt thereof).
Physical combinations include all admixtures as well as forms in which the essential components are separate and distinct. An example of the latter is a dosage form in which one component is in a substrate and the other is in a coating on the substrate. This type of dosage form is known and is prepared from the subject components in essentially the same manner as from other active ingredients.
Preferred combinations are those which contain the respective components of the active ingredient in a molar ratio of urapidil:furosemide in the range of from 5:1 to 1:5. Of these combinations, those having a ratio of such components in the range of from 3:1 to 1:3 are of particular interest, and those in which the ratio is 1:1 are outstandingly important.
The invention also relates to a method for treating hypertension in mammals, particularly in humans, which comprises administering a therapeutically-effective amount of the active ingredient according to the invention or of a medicament containing the active ingredient to a living organism, e.g. a male or female patient, afflicted with high blood pressure.
Such medicament, formulated according to processes known to those skilled in the art, is optionally in any standard dosage form suitable for a recognized mode of administration. It is preferably administered orally or parenterally injected, e.g., subcutaneously, intramuscularly or intravenously. Pharmaceutical preparations based on the active ingredient are advantageously in unit dosage form adapted for the desired mode of administration. A unit dose is, e.g. a tablet, a capsule or a measured volume amount of a powder, a granulate or a solution. "Unit dose", in the sense of the present invention, is a physically-specified unit which contains an individual amount of active ingredient (combination of urapidil with furosemide) in admixture with a pharmaceutical diluent therefor or together with a pharmaceutical excipient. The amount of active ingredient is selected so that one or more units are usually enough for an individual therapeutic administration.
The unit dose, however, is optionally subdivisible, e.g. in the case of tablets provided with grooves, when only a fraction, such as a half or a quarter, of the subdivisible unit is needed for a single therapeutic administration.
Pharmaceutical preparations according to the invention contain, when they are present in unit dosage form, a total of from 5 to 150, advantageously from about 25 to 100 and, in particular, from about 40 to 70 , milligrams (mg) of active ingredient. Therapeutic administration of such pharmaceutical preparations is effected 1 or several, e.g. three, times daily, e.g. after each meal and/or in the evening. Administration may, however, particularly in the case of application as a maintenance dose, be effected only on every second day.
The actual dose administered is governed by the frequency of administration, by the duration of treatment, by the nature and gravity of the illness and by the weight, age and state of health of the subject. In general, the daily (oral) dose for mammals, e.g. humans, lies between about 0.1 and 1.0 mg of active ingredient per kilogram (kg) of body weight.
the pharmaceutical preparations generally comprise active ingredient according to the invention and non-toxic, pharmaceutially-acceptable medicament excipient (used as additive in solid, semi-solid or liquid form or as surrounding agent, for example in the form of a capsule, a tablet coating, a bag or other container for the therapeutically-active constituent). An excipient optionally serves, e.g., as intermediary for the uptake of the medicament by the body, as formulation auxiliary, as sweetener, as flavoring, as coloring matter or as preservative.
Oral dosage forms include tablets, dragees, hard and soft capsules (e.g. of gelatin), dispersible powders, granulates, aqueous and oily suspensions, emulsions, solutions and syrups.
Tablets contain inert diluents, e.g. calcium carbonate, calcium phosphate, sodium phosphate or lactose; granulating or distributing agent, e.g. maize starch or alginate; binder, e.g. starch, gelatin or acacia gum; and/or lubricant, e.g. aluminum or magnesium stearate, talc or silicone oil. They are optionally additionally provided with a coating which, e.g., is of such a nature that it causes delayed dissolving and resorption of the medicament in the gastro-intestinal tract and thus, e.g., better compatibility or an extended duration of action. Gelatin capsules contain, e.g., the active ingredient in admixture with a solid diluent, e.g. calcium carbonate or kaolin, or an oily diluent, e.g. olive oil, arachis oil or paraffin oil.
Illustrative suspending agents are, e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia gum; dispersing and wetting agents include, e.g., polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylenesorbitol mono-oleate, polyoxyethylenesorbitan mono-oleate and lecithin; preservatives comprise, e.g., methyl or propyl hydroxybenzoates; sucrose, lactose, dextrose and invert sugar syrup are typical of flavoring and sweetener.
Oily suspensions contain, e.g., arachis oil, olive oil, sesame oil, coconut oil or paraffin oil and thickener, such as beeswax, hard paraffin or cetyl alcohol, in addition to sweetener, flavoring and antioxidant.
Powders and granulates which are dispersible in water optionally contain the active ingredient in admixture with dispersing, wetting and suspending agents, e.g. those previously mentioned, as well as with sweetener, flavoring and coloring matter.
Emulsions contain, e.g., olive oil, arachis oil or paraffin oil besides emulsifier, such as acacia gum, gum tragacanth, phosphatide, sorbitan mono-oleate, polyoxyethylenesorbitan mono-oleate, and sweetener and flavoring.
The different dosage forms are prepared according to well-established procedures by substituting the instant active ingredient in the desired amount for that in corresponding medicament compositions based on other active ingredients having similar or different pharmacological activity.
Parenterally, the medicaments are administered as sterile solutions, e.g., isotonic salt solutions comprising dispersing and/or wetting agents and/or pharmacologically compatible diluting agents, as for example kollidon. They are optionally bottled in the form of continuous intravenous drip bottles for continuous intravenous administration.
The active ingredient and medicament containing same (according to the invention) are very well suited for therapeutic application. Exploratory tests on male and female patients with hypertension (varying in origin and differing in degree of gravity) resulted in normalizing blood pressure in the majority of hypertensive persons to which the active ingredient was administered. Further, superiority (compared to urapidil) of medicament according to the invention was observed with regard to increased activity maximum, reduced side effects, e.g. urine excretion and electrolyte excretion, and reduced toxicity. The active ingredient and medicament according to the invention therefore represent a substantial advance in the treatment of hypertension.
The preparation of the active ingredient is effected according to processes which are known per se to one skilled in the art. For example, the 1:1 furosemide salt of urapidil is obtained by direct reaction of equimolar amounts of furosemide and urapidil dissolved in suitable solvents. Such solvents include aliphatic alcohols, such as methanol, ethanol and ethyl cellosolve; chlorinated hydrocarbons, such as methylene chloride and chloroform; aliphatic carboxylic acid amides or nitriles, such as dimethyl formamide, dimethyl acetamide and acetonitrile; aliphatic ketones, such as acetone and methyl ethyl ketone; or mixtures thereof.
The 1:1 urapidil/furosemide is, however, also obtained by resalting, e.g. by reaction of an appropriate urapidil salt, such as a hydrohalide, preferably the hydrochloride, with a suitable salt of furosemide, such as an alkali-metal salt, preferably the sodium salt, or the ammonium salt. The starting materials, dissolved in suitable solvents, are added to one another. Sufficient differences in solubility between the strating product and end product are essential, and the inorganic salt formed as a by-product, e.g. sodium chloride, should be readily separable. Suitable solvents for the resalting are, for example, water, lower aliphatic alcohols (such as methanol and ethanol), aliphatic ketones (such as acetone and methyl ethyl ketone), carboxylic acide amides or nitriles (such as dimethylformamide, dimethylacetamide and acetonitrile) or mixtures thereof with water.
By treating hypertension with a combination of urapidil and furosemide, a mode of treatment is provided which is sufficiently effective and compatible for wide therapeutic use. The invention relates to combinations (physical and/or chemical) of urapidil and furosemide, to medicaments (including pharmacologically-acceptable hypotensive compositions) containing such combinations and useful for reducing the blood pressure of mammals afflicted with hypertension and to a method of treating hypertension in mammals, particularly humans, by administering to a living afflicted organism, such as a male or female patient, a therapeutically-effective amount of such a combination or of a medicament containing same.
As a result of a synergistic effect of the essential components of the active ingredient on one another, the amount of active ingredient administered and, therefore, to be metabolized, i.e. the active ingredient loading of the patient, is greatly reduced. The medicament according to the invention therefore represents a substantial advance in the treatment of hypertension.
The following examples are entirely illustrative in nature and in no way limit the invention to which the appended claims are directed.
EXAMPLE 1 1,3-dimethyl-4-[3-(1-o-methoxyphenylpiperazinyl-4)-propylamino]uracil-[2-(2-furylmethyl)amino-4-chloro-5-sulfamylbenzoate] (salt)
Dissolve 584 g (1.5 moles) of hot (45° to 50° C) 1,3-dimethyl-4-(γ-[4-(o-methoxyphenyl)piperazinyl-(1)]-propylamino)uracil (urapidil) in 3 liters of methanol and 1 liter of chloroform and add thereto a hot (45° to 50° C) suspension of 500 g (1.5 moles) of 2-(2-furylmethyl)amino-4-chloro-5-sulfamylbenzoic acid (furosemide) in 1 liter of methanol. In a short time the resulting mixture forms a clear solution from which the title 1:1 acid-addition salt immediately begins to crystallize out. Draw off half of the solvent mixture in a vacuum; cool the remaining slurry of crystals for a further period on an ice-(sodium chloride) mixture and then suction filter it. Wet the residue with methanol and dry filter cake in a vacuum at 80° C to obtain, in this manner, 1,078.6 grams (g) of the title salt, m.p.: 219° C, corresponding to a yield of 99.5% of theory.
EXAMPLE 2 1,3-dimethyl-4-[3-(1-o-methoxyphenylpiperazinyl-4)-propylamino]uracil-[2-(2-furylmethyl)amino-4-chloro-5-sulfamylbenzoate] (salt)
Dissolve 331.7 g (1mole) of furosemide and 44 g (1.1 moles) of caustic soda in 3 liters of water, with heating. With constant stirring, add to this solution of solution of 387.5 g (1 mole) of urapidil in 550 milliliters (ml) of 2N hydrochloric acid and 2,150 ml of water. The title 1:1 acid-addition salt crystallizes out even during the mixing of the solutions. Cool the thus-obtained salt mixture to 0° C, suction filter the resulting slurry of crystals and wash the obtained filter cake several times with ice-cold water until the filtrate is chloride-free. Dry the product in a vacuum at 80° C to obtain 699.8 g of the title salt, m.p.: 219° C, corresponding to a yield of 97.3% of theory.
EXAMPLE 3 Tablets with 50 mg of salt
Production of a batch of 100,000 tablets, each of 50 milligrams (mg) of salt:
______________________________________                                    
1. salt                  5.0 kg                                           
2. maize starch          8.2 kg                                           
3. lactose               4.8 kg                                           
4. highly-disperse silicic acid                                           
                         0.3 kg                                           
5. sodium lauryl sulfate 0.4 kg                                           
6. gelatin               0.5 kg                                           
7. glycerin              0.1 kg                                           
8. talc                  0.5 kg                                           
9. magnesium stearate    0.2 kg                                           
                         20.0 kg                                          
______________________________________
Mix and finely grind 1 and 3. Mix the resulting admixture with 4, 5 and 7 kilograms (kg) of 2. Moisten the thus-obtained powder mixture with a solution of 6 and 7 in 7 liters of water and then pass it through a sieve of mesh size 1.25 millimeter (mm). Dry and then mix the resulting granulate well with the remainder of 2, 8 and 9 before compressing it into tablets, each of 200 mg.
EXAMPLE 4 Dragees with 25 mg of salt
Production of a batch of 400,00 varnished tablets:
______________________________________                                    
1. salt                 10.0 kg                                           
2. lactose              32.0 kg                                           
3. potato starch        8.0 kg                                            
4. polyvinylpyrrolidone 2.8 kg                                            
5. polyethyleneglycol 4000                                                
                        2.0 kg                                            
6. talc                 1.6 kg                                            
7. magnesium stearate   0.8 kg                                            
8. Primojel             2.8 kg                                            
                        60.0 kg                                           
______________________________________
Mix 1 with 2 and 3 and then sieve the obtained powder mixture. Dissolve 4 and 5 in 6 liters of ethanol and 4 liters of water. Moisten the powder mixture with this solution and then pass it through a sieve of mesh size 1.25 mm. Dry and then mix the resulting granulate with 6, 7 and 8 before compressing the prepared admixture into dragee cores, each of 150 mg. Coat these cores in a coating pan with the following suspension:
______________________________________                                    
1. methylcellulose      1.8 kg                                            
2. shellac              0.3 kg                                            
3. polyvinylpyrrolidone 0.3 kg                                            
4. polyethyleneglycol 4000                                                
                         0.01 kg                                          
5. titanium dioxide      0.29 kg                                          
6. amaranth red         0.3 kg                                            
7. isopropanol          10 liters                                         
8. methylene chloride   10 liters                                         
______________________________________
EXAMPLE 5 Capsules with 30 mg of salt
Production of a batch of 100,000 capsules:
______________________________________                                    
       1. salt        3.0 kg                                              
       2. lactose     4.2 kg                                              
       3. Primojel    1.5 kg                                              
       4. Kollidon    0.3 kg                                              
______________________________________
Carefully mix and finely grind 1,2 and 3. Dissolve 4 in 3 liters of water. Moisten the ground powder mixture with this solution and pass it through a sieve of 1.25 mm mesh size. Dry the resulting granulate and then fill size 4 capsules with 90 mg (each) of such granulate.
EXAMPLE 6 Tablets with 50 mg of combination
Production of a batch of 100,000 tablets
______________________________________                                    
1.      urapidil             2.7 kg                                       
2.      furosemide           2.3 kg                                       
3.      maize starch         8.2 kg                                       
4.      lactose              4.8 kg                                       
5.      highly-disperse silicic acid                                      
                             0.3 kg                                       
6.      sodium lauryl sulfate                                             
                             0.4 kg                                       
7.      gelatin              0.5 kg                                       
8.      glycerin             0.1 kg                                       
9.      talc                 0.5 kg                                       
10.     magnesium stearate   0.2 kg                                       
______________________________________
Mix and finely grind 1, 2 and 4. Mix this mixture with 5, 6 and 7 kg of 3. Moisten the resulting powder mixture with a solution of 7 and 8 in 7 liters of water and pass it through a sieve of mesh size 1.25 mm. Dry the thus-obtained granulate before mixing it well with the remainder of 3, 9 and 10 and compressing the resultant into tablets, each of 200 mg.
EXAMPLE 7 Dragees with 50 mg of combination
Production of a batch of 400,000 varnished tablets:
______________________________________                                    
1. urapidil             15.56 kg                                          
2. furosemide           4.44 kg                                           
3. lactose              22.00 kg                                          
4. potato starch        8.00 kg                                           
5. polyvinylpyrrolidone 2.80 kg                                           
6. polyethyleneglycol 4000                                                
                        2.00 kg                                           
7. talc                 1.60 kg                                           
8. magnesium stearate   0.80 kg                                           
9. Primojel             2.80 kg                                           
                        60.00 kg                                          
______________________________________
Mix 1 and 2 with 3 and 4 and then sieve the resulting powder mixture. Dissolve 5 and 6 in 6 liters of ethanol and 4 liters of water. Moisten the powder mixture with this solution and pass it through a sieve of mesh size 1.25 mm. Dry the thus-obtained granulate before mixing it with 7, 8 and 9. Compress the resultant into dragee cores, each of 150 mg, and coat them in a coating pan with the following suspension:
______________________________________                                    
1. methylcellulose      1.8 kg                                            
2. shellac              0.3 kg                                            
3. polyvinylpyrrolidone 0.3 kg                                            
4. polyethyleneglycol 4000                                                
                         0.01 kg                                          
5. titanium dioxide      0.29 kg                                          
6. isopropanol          10 liters                                         
7. methylene chloride   10 liters                                         
______________________________________
EXAMPLE 8 Tablets with 50 mg of combination
Production of a batch of 100,000 tablets:
______________________________________                                    
1.     urapidil               1.4 kg                                      
2.     furosemide             3.6 kg                                      
3.     potato starch          10.3 kg                                     
4.     polyvinylpyrrolidone                                               
       (average molecular weight 25,000)                                  
                              0.5 kg                                      
5.     carboxymethylcellulose 1.8 kg                                      
6.     magnesium stearate     0.2 kg                                      
7.     talc                   4.5 kg                                      
                              22.3 kg                                     
______________________________________
Spray the weighed amounts of 1, 2 and 3 (in a GLATT fluidized-bed granulator) with a solution of 4 in 5 liters of water. After drying to a relative moisture content of from 50 to 60%, add constituents 5 and 6 thereto and homogeneously mix. After sieving, compress the resulting granulate into tablets, each of 223 mg and having an 8 mm diameter.
EXAMPLE 9 Capsules with 30 mg of combination
Production of a batch of 100,000 capsules:
______________________________________                                    
1. urapidil            1.62 kg                                            
2. furosemide         1.38 kg                                             
3. lactose            4.2 kg                                              
4. Primojel           1.5 kg                                              
5. Kollidon           0.3 kg                                              
                      9.0 kg                                              
______________________________________
Carefully mix and finely grind 1, 2, 3, and 4 to produce a powder mixture. Dissolve 5 in 3 liters of water. Moisten the powder mixture with this solution and pass it through a sieve of mesh size 1.25 mm. Dry the resulting granulate and then fill size 4 capsules with 90 mg (each) of such granulate.
The following pharmacological data verify the superiority of the salt according to the invention and the superiority of the combinations according to the invention over the individual components.
For the determination of the antihypertensive action, the compounds or mixtures are administered daily, by means of oesophageal sound, in the stated doses on the stated number of consecutive days, to, in each case, eight rats (OKAMOTO strain) with genetically caused hypertension. The measurement of the blood pressure was effected, in each case, 2, 6 and 24 hours after administration of the substance.
The measurement of the systolic blood pressure was effected with the aid of an inflatable cuff place around the tail root, on which cuff there are arranged distally annularly 3 piezoelectric crystals (at a distance of 120° ) for registering the pulse waves. The determination of the blood pressure was effected by inflation of the cuff and graphic recording of the pulse amplitude.
The animals were kept in, and the experiments were carried out in, an ambience of 26° C and an atmospheric humidity of 60%. To accustom them to the measuring process, the animals were habituated to the measuring process 2 - 3 times daily for three days. For this purpose, as in the following experiments, the rats were put into tunnel-shaped wire cage; one narrow side of the cages is slidable, the other has an opening for the taking through of the tail. In order to ensure a blood flow through the tail artery during the measurement, the tails are irradiated for 5 - 10 minutes with a red-light lamp (150 watts) (distance: animal - lamp = 50 cm). Air temperature in the immediate region of the tail was 30 - 33° C. The body of the animals is protected from direct irradiation by plastic disks which are arranged about 10 cm above the cages.
From Table 1, in which the influence of urapidil, furosemide and of the salt on the systolic blood pressure of genetically hypertonic rats is compiled, it is seen that the salt according to the invention has an excellent antihypertensive action with a dose at which the component urapidil, exhibits only a slight effect and the component, furosemide, exhibits no effect. The salt exhibits, according to Table 1, a synergistic, i.e. a superadditive, action compared to that of the individual constituents.
From Table 2 it is seen that the combinations, according to the invention, of urapidil with furosemide exhibit an excellent antihypertensive action with doses at which the individual components have little or no effect. From the Table it emerges unambiguously that furosemide exerts a synergistic effect on the hypotensive action of urapidil. In the case of combinations of practically ineffective doses of urapidil or furosemide, an antihypertensive effect is obtained which is more pronounced than that of larger amounts of urapidil alone.
The combinations have the advantage that they -- because of their reduced doses of urapidil -- do not show the side effects of urapidil, e.g. sedation, but do exert a pronounced antihypertensive action.
                                  Table 1                                 
__________________________________________________________________________
Influence of urapidil, furosemide and salt* on the systolic blood         
pressure of                                                               
genetically hypertonic rats                                               
                                    Average                               
                                         Average change**** of            
                                Days                                      
                                    blood                                 
                                         blood pressure                   
Dose**    Urapidil proportion                                             
                    Furosemide proportion                                 
                                admini-                                   
                                    pressure                              
                                         (mm Hg) after                    
Substance                                                                 
      mg/kg                                                               
          mg/kg     mg/kg       stered                                    
                                    SV***                                 
                                         2 hrs.                           
                                             6 hrs.                       
                                                 24 hrs.                  
__________________________________________________________________________
Salt* 10  5.4       4.6         4   197  -31 -30 -6                       
Furosemide                                                                
      9.2 0         9.2         14  190  + 1 - 4 +4                       
Urapidil                                                                  
      10  10        0           8   206  -17 -15 -6                       
__________________________________________________________________________
 *Salt: compound according to Example 1                                   
 **daily administraton of a single dose                                   
 ***SV: starting values (mm Hg)                                           
 ****calcuated by summing up the values obtained after the indicated hours
 after each administration and dividing the sum by the days of            
 administration                                                           

                                  Table 2                                 
__________________________________________________________________________
Influence of urapidil, furosemide and their combinations on the systolic  
blood pressure of                                                         
genetically hypertonic rates                                              
                                      Average                             
                                           Average change*** of           
Substance                         Days                                    
                                      blood                               
                                           blood pressure                 
or      Dose*                                                             
            Urapidil proportion                                           
                      Furosemide proportion                               
                                  admini-                                 
                                      pressure                            
                                           (mm Hg) after                  
combination                                                               
        mg/kg                                                             
            mg/kg     mg/kg       stered                                  
                                      SV** 2 hrs.                         
                                               6 hrs.                     
                                                   24 hrs.                
__________________________________________________________________________
Urapidil (U)                                                              
        10  10        0           8   206  -17 -15 -6                     
Furosemide (F)                                                            
        9.22                                                              
            0         9.22        14  190  + 1 - 4 +4                     
U/F                                                                       
molar ratio                                                               
1:3     10  2.8       7.2         4   190  -22 -22 -1                     
U/F                                                                       
molar ratio                                                               
1:1     10  5.4       4.6         4   197  -31 -30 -6                     
U/F                                                                       
molar ratio                                                               
3:1     10  7.8       2.2         4   201  -39 -36 -15                    
__________________________________________________________________________
 *daily administration of a single dose                                   
 **SV: starting values (mm/Hg)                                            
 ***calculated by summing up the values obtained after the indicated hours
 after each administration and dividing the sum by the days of            
 administration
For the determination of the acute toxicity, the compounds and mixtures were suspended by ultrasonic methods in 1% strength solution of Tylose. Of the suspensions, in each case 40 ml/kg were administered to, in each case, 5 female albino mice (NMRI).
From Table 3, in which the lethal effect (in %) of urapidil and of the salt, in dependence on the dose, is reproduced, it is seen that the salt is substantially less toxic than urapidil. Thus, e.g. 5000 mg/kg of salt with a urapidil proportion of 2690 mg/kg have no lethal effect, whereas 1076 mg/kg of urapidil already cause a lethality of 80% and 1614 mg/kg of urapidil cause a lethality of 100%.
              Table 3                                                     
______________________________________                                    
Lethal effect of urapidil and of the salt of the formula I on             
the female albino mouse                                                   
        Dose      Urapidil   Furosemide                                   
        total     proportion proportion                                   
                                      Lethality                           
Substance                                                                 
        (mg/kg)   (mg/kg)    (mg/kg)  (%)                                 
______________________________________                                    
Urapidil                                                                  
         538       538       --       0                                   
Salt.sup.(+)                                                              
        1000       538        462     0                                   
Urapidil                                                                  
        1076      1076       --       80                                  
Salt.sup.(+)                                                              
        2000      1076        924     0                                   
Urapidil                                                                  
        1614      1614       --       100                                 
Salt.sup.(+)                                                              
        3000      1614       1386     0                                   
Urapidil                                                                  
        2152      2152       --       100                                 
Salt.sup.(+)                                                              
        4000      2152       1848     0                                   
Salt.sup.(+)                                                              
        5000      2690       2310     0                                   
______________________________________                                    
 .sup.(+) Salt: compound according to Example 1
From Table 4, in which the lethal effect (in %) of urapidil and of a combination in the molar ratio 1:1 is reproduced, it can be seen that the combination is substantially less toxic than urapidil. Thus, the administration of 5000 mg/kg of the 1:1 combination (urapidil proportion 2690 mg/kg) leads to no death (lethality = 0%) whereas, when alone 1076 mg/kg of urapidil is administered, the lethality is already 80% and, with 1614 mg/kg of urapidil, the lethality is 100%.
              Table 4                                                     
______________________________________                                    
Lethal effect of urapidil                                                 
and of its combination with the furosemide in the                         
molar ratio 1:1 on the female albino mouse                                
         Dose      Urapidil   Furosemide                                  
         total     proportion proportion                                  
                                      Lethality                           
Substance                                                                 
         (mg/kg)   (mg/kg)    (mg/kg) (%)                                 
______________________________________                                    
Urapidil  538      538        --      0                                   
Combination                                                               
         1000      538         462    0                                   
Urapidil 1076      1076       --      80                                  
Combination                                                               
         2000      1076        924    0                                   
Urapidil 1614      1614       --      100                                 
Combination                                                               
         3000      1614       1386    0                                   
Urapidil 2152      2152       --      100                                 
Combination                                                               
         4000      2152       1848    0                                   
Combination                                                               
         5000      2690       2310    0                                   
______________________________________
From Table 5, in which the influence of urapidilfurosemide combinations with various furosemide content on the survival rate of female albino mice is reproduced, it can be seen that the toxicity of urapidil is considerably reduced by additions of furosemide. Whereas the survival rate with administration of 1500 mg/kg of urapidil on its own is zero, with constant proportion of urapidil the survival rate rises with increasing addition of furosemide. Already with a molar ratio of urapidil: furosemide of 5:1, the servival rate is 40%. The protective action of the furosemide manifests itself particularly clearly from a molar ratio of urapidil: furosemide of 3:1 onwards and reaches an optimum at a molar ratio of about 1:1.
              Table 5                                                     
______________________________________                                    
Influence of urapidil and its combinations with furosemide on the         
survival rate of female albino mice                                       
Urapidil dose                                                             
          Furosemide dose         Survival rate                           
(mg/kg)   (mg/kg)       Molar ratio                                       
                                  (%)                                     
______________________________________                                    
1500      --            --         0                                      
1500      180           7.1 : 1    0                                      
1500      250           5.1 : 1   40                                      
1500      360           3.6 : 1   60                                      
1500      500           2.6 : 1   60                                      
1500      720           1.8 : 1   80                                      
1500      1000          1.3 : 1   100                                     
1500      1200          1.1 : 1   100                                     
______________________________________
The invention and its advantages are readily understood from the foregoing description, from which it is apparent that various changes may be made in the components of the active ingredient, in the form of the active ingredient, in medicament containing the active ingredient and in the manner and mode of administering the active ingredient and such medicament without departing from the spirit and scope of the invention or sacrificing its material advantages. The products, the combinations of ingredients, the compositions and the methods of use hereinbefore described are merely illustrative of preferred embodiments of the invention.
Throughout the disclosure reference is made to a combination of two essential components. One of these components (in free-base form) is urapidil. The other (in free form) is furosemide. Furosemide is in free form whenever the carboxyl group is in -COOH form; Urapidil is in free-base form when it is not in the form of an acid-addition salt.

Claims (15)

What is claimed is:
1. A first component which, in free-base form, is urapidil in combination with a second component which, in free form, is furosemide; the proportion of the second component being sufficient to increase the effectiveness of the first as a hypotensive agent and the combination of the two components being physiologically active and pharmacologically-acceptable.
2. A combination according to claim 1 wherein the molar ratio of the first component to the second component is from 5:1 to 1:5.
3. A combination according to claim 1 wherein the second component is chemically combined with the first component.
4. A combination according to claim 3 in the form of the 1:1 furosemide acid-addition salt of urapidil.
5. A combination according to claim 1 wherein the molar ratio of the first component to the second component is from 3:1 to 1:3.
6. A physical combination according to claim 1 wherein the molar ratio of the first component to the second component is 1:1.
7. A combination according to claim 2 comprising a physical admixture of furosemide with urapidil.
8. A blood-pressure reducing medicament for subjects afflicted with hypertension and which comprises an effective concentration of a combination according to claim 1 and suitable diluent or excipient.
9. Medicament according to claim 8 in unit dosage form.
10. A pharmacologically-acceptable composition having a physiologically-active component and at least one component which is essentially therapeutically inactive, the active component comprising an effective concentration of a combination according to claim 1.
11. A process which comprises administering to a mammal afflicted with hypertension a blood-pressure-reducing amount of a combination according to claim 1.
12. A process according to claim 11 wherein the mammal is a human.
13. A process for reducing the toxicity of urapidil which comprises combining therewith a toxicity-reducing amount of furosemide.
14. A process according to claim 13 which comprises physically combining furosemide with urapidil in a form in which the two are not chemically combined.
15. A process according to claim 13 which comprises chemically combining furosemide with urapidil.
US05/767,214 1976-02-09 1977-02-09 Urapidil/furosemide compounds, compositions and use Expired - Lifetime US4131678A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
LU74319A LU74319A1 (en) 1976-02-09 1976-02-09
LU74319 1976-02-09

Publications (1)

Publication Number Publication Date
US4131678A true US4131678A (en) 1978-12-26

Family

ID=19728151

Family Applications (1)

Application Number Title Priority Date Filing Date
US05/767,214 Expired - Lifetime US4131678A (en) 1976-02-09 1977-02-09 Urapidil/furosemide compounds, compositions and use

Country Status (20)

Country Link
US (1) US4131678A (en)
JP (2) JPS5296718A (en)
AT (1) AT347478B (en)
BE (1) BE851267A (en)
CA (1) CA1065865A (en)
CH (1) CH625792A5 (en)
DE (1) DE2704935C2 (en)
DK (1) DK52877A (en)
ES (1) ES455721A1 (en)
FI (1) FI61891C (en)
FR (1) FR2340316A1 (en)
GB (1) GB1512771A (en)
IE (1) IE44461B1 (en)
IL (1) IL51400A (en)
IT (1) IT1075919B (en)
LU (1) LU74319A1 (en)
NL (1) NL7701289A (en)
NO (1) NO145440C (en)
SE (1) SE7701441L (en)
YU (1) YU32477A (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4663348A (en) * 1985-07-02 1987-05-05 Warner-Lambert Co. Furosemide salts and pharmaceutical preparations thereof
US5034391A (en) * 1988-12-06 1991-07-23 Cl Pharma Aktiengesellschaft Piperazinylalkyl-3(2H)-pyridazinones and the use thereof as agents lowering blood pressure
CN100353944C (en) * 2004-06-24 2007-12-12 杨立新 Urapidil large volume injection, its preparation method and application

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58130183U (en) * 1982-02-26 1983-09-02 株式会社ブレスト工業研究所 Hanging equipment for air conditioning ducts, etc.
DE3902316A1 (en) * 1989-01-26 1990-08-02 Lentia Gmbh Novel piperazinylalkyl-3(2H)-pyridazinones, process for their preparation and their use as hypotensive agents
JP2815218B2 (en) * 1990-04-13 1998-10-27 三井化学株式会社 Pyrimidinedione derivatives and antiarrhythmic agents containing the same

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3058882A (en) * 1959-12-28 1962-10-16 Hoechst Ag N'-substituted-3-carboxy-6-halo-sulfanilamide and derivatives thereof
US3957786A (en) * 1969-08-20 1976-05-18 Byk Gulden Aryl-substituted piperazinyl-alkylamino-uracils, -uracil ethers and -uracil thioethers and method for their production

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5212560A (en) * 1975-07-21 1977-01-31 Hitachi Ltd Electronic beam probe control device

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3058882A (en) * 1959-12-28 1962-10-16 Hoechst Ag N'-substituted-3-carboxy-6-halo-sulfanilamide and derivatives thereof
US3957786A (en) * 1969-08-20 1976-05-18 Byk Gulden Aryl-substituted piperazinyl-alkylamino-uracils, -uracil ethers and -uracil thioethers and method for their production

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4663348A (en) * 1985-07-02 1987-05-05 Warner-Lambert Co. Furosemide salts and pharmaceutical preparations thereof
US5034391A (en) * 1988-12-06 1991-07-23 Cl Pharma Aktiengesellschaft Piperazinylalkyl-3(2H)-pyridazinones and the use thereof as agents lowering blood pressure
CN100353944C (en) * 2004-06-24 2007-12-12 杨立新 Urapidil large volume injection, its preparation method and application

Also Published As

Publication number Publication date
SE7701441L (en) 1977-08-10
JPS5296718A (en) 1977-08-13
JPS5713544B2 (en) 1982-03-17
DE2704935C2 (en) 1985-01-10
CH625792A5 (en) 1981-10-15
JPS5726618A (en) 1982-02-12
GB1512771A (en) 1978-06-01
ES455721A1 (en) 1978-01-01
FR2340316B1 (en) 1980-02-08
IL51400A (en) 1980-12-31
YU32477A (en) 1982-06-30
NL7701289A (en) 1977-08-11
BE851267A (en) 1977-08-09
FI770406A7 (en) 1977-08-10
FR2340316A1 (en) 1977-09-02
NO145440B (en) 1981-12-14
LU74319A1 (en) 1977-08-19
DK52877A (en) 1977-08-10
IT1075919B (en) 1985-04-22
IE44461B1 (en) 1981-12-02
NO770411L (en) 1977-08-10
DE2704935A1 (en) 1977-08-11
IE44461L (en) 1977-08-09
IL51400A0 (en) 1977-04-29
AT347478B (en) 1978-12-27
CA1065865A (en) 1979-11-06
FI61891C (en) 1982-10-11
FI61891B (en) 1982-06-30
NO145440C (en) 1982-03-24
ATA81777A (en) 1978-05-15

Similar Documents

Publication Publication Date Title
CA1228300A (en) Galenic preparation forms for oral antidiabetic agents and processes for producing them
JPS63258841A (en) Tyrosine derivative and use thereof
US5547970A (en) Use of leflunomide for inhibiting tumor necrosis factor alpha
US4131678A (en) Urapidil/furosemide compounds, compositions and use
US5663201A (en) Desferrioxamine-B salts
CA3181902A1 (en) Methods for treating or preventing chronic kidney disease
JPS604802B2 (en) anticancer drug
JPS6049629B2 (en) Production method of new amino acid derivatives
US3949082A (en) Thiadiazoles as anti-inflammatory agents
JPH0560447B2 (en)
CN108774220B (en) Compounds for treating myocardial ischemia and uses thereof
US3459854A (en) Tetracycline cyclohexyl sulphamate and process for preparation
JPH05504550A (en) Pyrimidine biosynthesis inhibitor useful as an immunosuppressant
JPH0326168B2 (en)
CN103664930B (en) One class is containing compound, the Preparation Method And The Use of thiazole structure
JPS63225381A (en) Liver disease treatment agent
SE502323C2 (en) Use of N- (2-hydroxyethyl) nicotinamide nitrate or a pharmaceutically acceptable salt thereof for the manufacture of a drug actively for the treatment of diseases associated with cerebral ischemia
JPS5857431B2 (en) Method for producing cerebral vasodilator 2,3-substituted-4-heterocyclic aminosulfonylbenzenesulfonamide
KR800000451B1 (en) Method for preparing benzenesulfonyl-urea
HU203839B (en) Process for producing pharmaceutical composition containing acrylic acid derivatives
JPS6056974A (en) Cyclic dithiodiacetamide, manufacture and drug
JPS5942377A (en) Dithiol derivative
JPS6041690A (en) 1-thio-beta-d-glucuronic acid derivative, its preparation and its use
JPH03232870A (en) thioamide compound
JPS6144818A (en) Antiarteriosclerotic agent